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Abstract Background Catechol-O-Methyltransferase (COMT) plays a key role in dopamine and estrogen metabolism. Recently, COMT haplotypes rather than the single polymorphism Val158Met have been reported to underlie differences in protein expression by modulating mRNA secondary structure. So far, studies investigating the epigenetic variability of the S-COMT (soluble COMT) promoter region mainly focused on phenotypical aspects, and results have been controversial. Methods We assessed S-COMT promoter methylation in saliva and blood derived DNA with regard to early pre- and postnatal growth as well as to genotype for polymorphisms rs6269, rs4633, and rs4680 (Val158Met) in 20 monozygotic twin pairs (mean age 4 years), who were discordant for intrauterine development due to severe feto-fetal-transfusion syndrome. Methylation levels of two previously reported partially methylated cytosines were determined by the quantitative SIRPH (SNuPE- IP RP HPLC) assay. Results Overall, we observed a high variability of S-COMT promoter methylation, which did not correlate with individual differences in the pre- or postnatal growth pattern. Within the twin pairs however we noted a distinct similarity that could be linked to underlying COMT genotypes. This association was subsequently confirmed in a cohort of 93 unrelated adult controls. Interestingly, 158Val-alleles were found at both ends of the epigenotypical range, which is in accordance with a recently proposed model of COMT haplotypes corresponding to a continuum of phenotypical variability. Conclusion The strong heritable component of S-COMT promoter methylation found in our study needs to be considered in future approaches that focus on interactions between COMT epigenotype and phenotype.

Platelet homeostasis is essential for vascular integrity and immune defence 1,2 . Although the process of platelet formation by fragmenting megakaryocytes (MKs; thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of MKs by their progenitor cells (megakaryopoiesis) remains unclear 3,4 . Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFNα to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This pDC-dependent feedback loop is crucial for MK and platelet homeostasis at steady state and under stress. pDCs are best known for their ability to function as vigilant detectors of viral infection 5 . We show that virus-induced activation of pDCs interferes with their function as homeostatic sensors of megakaryopoiesis. Consequently, activation of pDCs by SARS-CoV-2 leads to excessive megakaryopoiesis. Together, we identify a pDC-dependent homeostatic circuit that involves innate immune sensing and demand-adapted release of inflammatory mediators to maintain homeostasis of the megakaryocytic lineage., (© 2024. The Author(s).)

Plasmacytoid dendritic cells (pDCs) display an increased abundance in visceral adipose tissue (VAT) of humans with obesity. In the current study, we set out to decipher the molecular mechanisms of their recruitment to VAT and the functional relevance of this process. We observed increased pDC numbers in murine blood, liver, spleen, and VAT after feeding a high-fat diet (HFD) for 3 wk when compared with a standard diet. pDCs were enriched in fat-associated lymphoid clusters representing highly specific lymphoid regions within VAT. HFD led to an enlargement of fat-associated lymphoid clusters with an increased density and migratory speed of pDCs as shown by intravital multiphoton microscopy. For their recruitment into VAT, pDCs employed P-selectin with E-selectin and L-selectin being only critical in response to HFD, indicating that the molecular cues underlying pDC trafficking were dependent on the nutritional state. Subsequent recruitment steps required α 4 β 1 and α 4 β 7 integrins and engagement of CCR7. Application of fingolimod (FTY720) abrogated egress of pDCs from VAT, indicating the involvement of sphingosine-1-phosphate in this process. Furthermore, HFD altered pDC functions by promoting their activation and type 1 IFN expression. Blocking pDC infiltration into VAT prevented weight gain and improved glucose tolerance during HFD. In summary, a HFD fundamentally alters pDC biology by promoting their trafficking, retention, and activation in VAT, which in turn seems to regulate metabolism., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Loss of appetite (anorexia) is a typical behavioral response to infectious diseases that often reduces body weight. Also, anorexia can be observed in cancer and trauma patients, causing poor quality of life and reduced prospects of positive therapeutic outcomes. Although anorexia is an acute symptom, its initiation and endocrine regulation during antiviral immune responses are poorly understood. During viral infections, plasmacytoid dendritic cells (pDCs) produce abundant type I interferon (IFN-I) to initiate first-line defense mechanisms. Here, by targeted ablation of pDCs and various in vitro and in vivo mouse models of viral infection and inflammation, we identified that IFN-I is a significant driver of somatostatin (SST). Consequently, SST suppressed the hunger hormone ghrelin that led to severe metabolic changes, anorexia, and rapid body weight loss. Furthermore, during vaccination with Modified Vaccinia Ankara virus (MVA), the SST-mediated suppression of ghrelin was critical to viral immune response, as ghrelin restrained the production of early cytokines by natural killer (NK) cells and pDCs, and impaired the clonal expansion of CD8 + T cells. Thus, the hormonal modulation of ghrelin through SST and the cytokine IFN-I is fundamental for optimal antiviral immunity, which comes at the expense of calorie intake., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

In Japan and other Asian countries, increased fat uptake induced by a westernized diet is thought to be associated with an increased incidence of inflammatory bowel disease, colorectal cancer and food allergies; however, the mechanism for this remains unclear. High-fat diet (HFD)-fed mice are common animal models used to examine the effect of fat intake in vivo. HFDs are reported to exacerbate DSS-induced colitis and intestinal tumorigenesis, but the effect of HFDs on the intestines before disease induction is often overlooked. We found that the intestinal and gut-associated lymphoid tissue (GALT) morphology of HFD-fed mice differed from that of standard diet (SD)-fed mice. To clarify the mechanism by which fat intake increases intestinal diseases, we analyzed the morphological and immunological aspects of the intestines of HFD-fed mice as well as the molecular mechanisms and physiology. Feeding an HFD for 3 weeks induced atrophy of the small intestine, colon and GALT and reduced the number of small intestinal intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs). Feeding an HFD for only one day reduced the number of small intestinal (SI)-IELs and SI-LPLs. The effect of feeding a 3-week HFD continued for 2 weeks after returning to the SD. The effect of the HFD on the intestinal immune system was independent of the gut microbes. We hypothesized that the cytotoxicity of the abundant HFD-derived free fatty acids in the intestinal lumen impairs the intestinal immune system. Both saturated and unsaturated free fatty acids were toxic to intestinal T-cells in vitro. Orally administering free fatty acids reduced the number of SI-IELs and LPLs. Using a lipase inhibitor to reduce the luminal free fatty acids attenuated the HFD-induced changes in the intestinal immune system, while using a statin to reduce the serum free fatty acids did not. Thus, HFD-induced free fatty acids damaged the intestines; this effect was termed "intestinal lipotoxicity". Because sustained reduction of SI-LPLs after HFD feeding exacerbated indomethacin-induced small intestinal damage, lipotoxicity to the human intestines incurred by consuming a westernized diet in Japan may increase intestinal diseases such as IBD, colorectal cancer or food allergies., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A male patient with mosaic paternal uniparental diploidy (PUD) is presented. After birth, the patient presented with hypoglycemia, hemihypertrophy, umbilical hernia, and hepatomegaly. Afterward pancreatic hypertrophy, liver hemangiomas, and cysts were detected sonographically. At the age of 3.5 months, hepatoblastoma was diagnosed. To investigate suspected Beckwith-Wiedemann syndrome (BWS), extensive genetic analyses were performed using DNA from chorionic villus sampling, amniocentesis, and peripheral blood lymphocytes (chromosome analysis, methylation-specific multiplex ligation-dependent probe amplification assays, microsatellite analyses, and single nucleotide polymorphism array analysis). These analyses led to the detection of mosaic PUD. In peripheral blood lymphocytes, a male cell line (46,XY[27]/46,XX[5]) predominated, suggesting a mixture of uniparental isodisomy and heterodisomy. The genetic analyses suggest that the mosaic PUD status was attributable to fertilization of an oocyte by two sperms, with subsequent triploidy rescue giving rise to haploidy, which in turn was rescued. Notably, in the majority of the 28 mosaic PUD patients reported to date, BWS was initially suspected. Mosaic PUD status is associated with a higher risk for a broad range of malignant and benign tumors than in BWS. As tumors can also occur after childhood surveillance into adolescence is indicated. Mosaic PUD must therefore be considered in patients with suspected BWS., (© 2019 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.)

Chemokines have crucial roles in organ development and orchestration of leukocyte migration. The chemokine CCL22 is expressed constitutively at high levels in the lymph node, but the functional significance of this expression is so far unknown. Studying a newly established CCL22-deficient mouse, we demonstrate that CCL22 expression by dendritic cells (DCs) promotes the formation of cell-cell contacts and interaction with regulatory T cells (T reg) through their CCR4 receptor. Vaccination of CCL22-deficient mice led to excessive T cell responses that were also observed when wild-type mice were vaccinated using CCL22-deficient DCs. Tumor-bearing mice with CCL22 deficiency showed prolonged survival upon vaccination, and further, CCL22-deficient mice had increased susceptibility to inflammatory disease. In conclusion, we identify the CCL22-CCR4 axis as an immune checkpoint that is crucial for the control of T cell immunity., (© 2019 Rapp et al.)

Apoptotic cell death of Dendritic cells (DCs) is critical for immune homeostasis. Although intrinsic mechanisms controlling DC death have not been fully characterized up to now, experimentally enforced inhibition of DC-death causes various autoimmune diseases in model systems. We have generated mice deficient for Protein Phosphatase with EF-Hands 2 (Ppef2), which is selectively expressed in CD8 + DCs, but not in other related DC subtypes such as tissue CD103 + DCs. Ppef2 is down-regulated rapidly upon maturation of DCs by toll-like receptor stimuli, but not upon triggering of CD40. Ppef2-deficient CD8 + DCs accumulate the pro-apoptotic Bcl-2-like protein 11 (Bim) and show increased apoptosis and reduced competitve repopulation capacities. Furthermore, Ppef2 -/- CD8 + DCs have strongly diminished antigen presentation capacities in vivo , as CD8 + T cells primed by Ppef2 -/- CD8 + DCs undergo reduced expansion. In conclusion, our data suggests that Ppef2 is crucial to support survival of immature CD8 + DCs, while Ppef2 down-regulation during DC-maturation limits T cell responses.

Acute spinal cord injury (SCI) causes systemic immunosuppression and life-threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus-pituitary-adrenal axis stimulation. Instead of consecutive hypothalamus-pituitary-adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism. This neurogenic effect was more pronounced after high-thoracic level (Th1) SCI disconnecting adrenal gland innervation, compared with low-thoracic level (Th9) SCI. Prophylactic adrenalectomy completely prevented SCI-induced glucocorticoid excess and lymphocyte depletion but did not prevent pneumonia. When adrenalectomized mice were transplanted with denervated adrenal glands to restore physiologic glucocorticoid levels, the animals were completely protected from pneumonia. These findings identify a maladaptive sympathetic-neuroendocrine adrenal reflex mediating immunosuppression after SCI, implying that therapeutic normalization of the glucocorticoid and catecholamine imbalance in SCI patients could be a strategy to prevent detrimental infections.

Adipose tissue has a dynamic immune system that adapts to changes in diet and maintains homeostatic tissue remodeling. Adipose type 1 innate lymphoid cells (AT1-ILCs) promote pro-inflammatory macrophages in obesity, but little is known about their functions at steady state. Here we found that human and murine adipose tissue harbor heterogeneous populations of AT1-ILCs. Experiments using parabiotic mice fed a high-fat diet (HFD) showed differential trafficking of AT1-ILCs, particularly in response to short- and long-term HFD and diet restriction. At steady state, AT1-ILCs displayed cytotoxic activity toward adipose tissue macrophages (ATMs). Depletion of AT1-ILCs and perforin deficiency resulted in alterations in the ratio of inflammatory to anti-inflammatory ATMs, and adoptive transfer of AT1-ILCs exacerbated metabolic disorder. Diet-induced obesity impaired AT1-ILC killing ability. Our findings reveal a role for AT1-ILCs in regulating ATM homeostasis through cytotoxicity and suggest that this function is relevant in both homeostasis and metabolic disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

To evaluate body composition, metabolism and growth as well as their interaction with early nutrition in former extremely low birth weight infants (ELBW), we assessed qualitative and quantitative nutritional intake during initial hospitalization and infantile growth parameters in 61 former ELBW infants with a birth weight <1000 g. In two follow-up exams, physical and biochemical development were measured at 5.7 and at 9.5 years. At the second follow-up, in addition to biochemical reassessment, body composition was analyzed by dual-energy x-ray absorptiometry (DEXA). Protein intake between birth and discharge was associated with weight gain in the first six months of life ( r = 0.51; p < 0.01). Weight catch-up preceded height catch-up. Protein intake in early infancy correlated highly significantly with abdominal fat mass ( r = 0.49; p < 0.05), but not with lean body mass at 9.5 years ( r = 0.30; not significant (n.s.). In contrast to nutrient intake, birth weight was associated with lean body mass ( r = 0.433; p < 0.001). Early protein and carbohydrate intake were associated with high-density lipoprotein (HDL)-cholesterol, and early catch-up growth correlated with fasting insulin at follow-up. Stepwise linear regression demonstrated that protein intake predicted fat mass ( p < 0.05), whereas only gender and birth weight standard deviation score (SDS) contributed significantly to lean body mass variation ( p < 0.05). Our results suggest an important impact of early nutrient intake on body composition and metabolism in later childhood in ELBW children.

Cell division cycle 42 (Cdc42) is a member of the Rho guanosine triphosphatase family and has pivotal functions in actin organization, cell migration, and proliferation. To further study the molecular mechanisms of dendritic cell (DC) regulation by Cdc42, we used Cdc42-deficient DCs. Cdc42 deficiency renders DCs phenotypically mature as they up-regulate the co-stimulatory molecule CD86 from intracellular storages to the cell surface. Cdc42 knockout DCs also accumulate high amounts of invariant chain-major histocompatibility complex (MHC) class II complexes at the cell surface, which cannot efficiently present peptide antigens (Ag's) for priming of Ag-specific CD4 T cells. Proteome analyses showed a significant reduction in lysosomal MHC class II-processing proteins, such as cathepsins, which are lost from DCs by enhanced secretion. As these effects on DCs can be mimicked by chemical actin disruption, our results propose that Cdc42 control of actin dynamics keeps DCs in an immature state, and cessation of Cdc42 activity during DC maturation facilitates secretion as well as rapid up-regulation of intracellular molecules to the cell surface., (© 2015 Schulz et al.)

Background: Events during foetal or early extrauterine life may affect bodily structure and/or functions and even pave the way for adult diseases., Aims: To find whether extremely low birth weight (ELBW) infants differ from healthy controls regarding the excretion of steroid metabolites., Methods: The study compared 17 female and 10 male ELBW infants, all prepubertal, aged 8-11 years, birth weight <1,000 g, with 27 age- and sex-matched controls. All were healthy at the time of the study. Height, weight and BMI did not differ between the groups. Results were adjusted according to body surface area. 36 urinary steroid metabolites were quantified by gas chromatography-mass spectrometry., Results: In the ELBW girls 33/36 steroid metabolites were higher (19 significantly) than in the controls. All 36 steroid metabolites were higher in the ELBW boys (9 significantly) than in the controls. Sums of mineralocorticoid precursors, metabolites descriptive for cortisol and parameters of adrenal androgen production were significantly higher in ELBW infants (both sexes). Only the sum of the metabolites known to be illustrative for adrenal 11β-hydroxysteroid dehydrogenase activity was not different., Conclusion: Prepubertal ELBW children have an augmented urinary excretion of adrenal androgens, cortisol and mineralocorticoid precursors. These findings corroborate and help to explain the link between early-life adversity and subsequent adrenocortical function., (© 2015 S. Karger AG, Basel.)

Background: Prenatal growth restriction and low birth weight have been linked to long-term alterations of health, presumably via adaptive modifications of the epigenome. Recent studies indicate a plasticity of the 11p15 epigenotype in response to environmental changes during early stages of human development., Study Design: We analyzed methylation levels at different 11p15 loci in 20 growth-discordant monozygotic twin pairs. Intrauterine development was discordant due to severe twin-to-twin transfusion syndrome (TTTS), which was treated by fetoscopic laser coagulation of communicating vessels before 25 weeks of gestation. Methylation levels at age 4 were determined in blood and buccal cell-derived DNA by the single nucleotide primer extension reaction ion pair reverse-phase high performance liquid chromatography (SNuPE IP RP HPLC) assay. Methylation at LINE-1 repeats was analyzed as an estimate of global methylation., Results: In general, variance of locus-specific methylation levels appeared to be higher in buccal cell- as compared to blood cell-derived DNA samples. Paired analyses within the twin pairs revealed significant differences at only one CpG site (IGF2 dmr0 SN3 (blood), +1.9% in donors; P = 0.013). When plotting the twin pair-discordance in birth weight against the degree of discordance in site-specific methylation at age 4, only a few CpGs were found to interact (one CpG site each at IGF2dmr0 in blood/saliva DNA, one CpG at LINE-1 repeats in saliva DNA), with 26 to 36% of the intra-twin pair divergence at these sites explained by prenatal growth discordance. However, across the entire cohort of 40 children, site-specific methylation did not correlate with SD-scores for weight or length at birth. Insulin-like growth factor-II serum concentrations showed significant within-twin pair correlations at birth (R = 0.57) and at age 4 (R = 0.79), but did not differ between donors and recipients. They also did not correlate with the analyzed 11p15 methylation parameters., Conclusion: In a cohort of 20 growth-discordant monozygotic twin pairs, severe alteration in placental blood supply due to TTTS appears to leave only weak, if any, epigenetic marks at the analyzed CpG sites at 11p15.

Aim: To examine the impact of postnatal nutrition on long-term growth in extremely low birth weight infants., Method: Retrospective analysis of postnatal nutrition and observational study of growth in 52 ELBW infants until the age of six., Results: Changes (Δ) in weight and length standard deviation scores (SDS) between birth to term correlated with protein intake (r(w) = 0.36; p = 0.009; r(L) = 0.35; p = 0.01), whereas ΔHC correlated with lipid intake (r(HC) = 0.38; p = 0.005). Analysis of various intervals (0-2, 3-5, 6-8 and 9-11 weeks) only showed significant impact on growth for energy (r = 0.3; p < 0.05) and lipids (r = 0.23; p < 0.05) at 6-8 weeks. No significant correlations were found between postnatal nutritional parameters and long-term growth. However, postnatal growth restraint was negatively associated with length SDS (r = -0.34; p = 0.015) and body mass index SDS (r = -0.34; p = 0.018) at the age of six. Infants with postnatal growth restraint (n = 25) caught up more in length (+1.78 SDS) than in weight (+0.43 SDS), whereas small for gestational age infants (n = 8) caught up more in weight (+1.35 SDS) than in length (+1.07 SDS). This difference remained significant at the age of six., Conclusion: Although no direct association between postnatal nutrition and long-term growth was found, weight at discharge was a strong predictor for long-term growth., (©2013 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

T cells are activated by antigen (Ag)-bearing dendritic cells (DCs) in lymph nodes in three phases. The duration of the initial phase of transient, serial DC-T cell interactions is inversely correlated with Ag dose. The second phase, characterized by stable DC-T cell contacts, is believed to be necessary for full-fledged T cell activation. Here we have shown that this is not the case. CD8⁺ T cells interacting with DCs presenting low-dose, short-lived Ag did not transition to phase 2, whereas higher Ag dose yielded phase 2 transition. Both antigenic constellations promoted T cell proliferation and effector differentiation but yielded different transcriptome signatures at 12 hr and 24 hr. T cells that experienced phase 2 developed long-lived memory, whereas conditions without stable contacts yielded immunological amnesia. Thus, T cells make fate decisions within hours after Ag exposure, resulting in long-term memory or abortive effector responses, correlating with T cell-DCs interaction kinetics., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Hyperglycemic hyperosmolar coma diabeticum (HHS) is a rare phenomenon in pediatric patients. It causes major morbidity and significant mortality. It is characterized by the trias of hyperglycemia, hyperosmolality and absent or mild metabolic acidosis. Major complications include cerebral edema and rhabdomyolysis. Evidence based guidelines for HHS in children are lacking. Based on a literature review we discuss treatment options in pediatric HHS und suggest a therapeutic concept. Appropriate treatment consists of adequate fluid administration and a cautious lowering of the serum glucose level. Patients should be treated on an intensive care unit and monitored closely to avoid complications. Low-dose and late insulin administration seems to be favourable., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Low birth weight predisposes to the development of insulin resistance. In addition to auxological parameters such as rapid catch-up growth, low IGFBP-1 serum levels in childhood have been linked to an increased risk of insulin resistance later in life. Concerning postnatal growth, we previously reported the GHRd3-variant to be associated with catch-up growth in preterm infants. In children born small for gestational age, a common IGFBP-1 promoter polymorphism -575G/A has been linked to IGFBP-1 serum levels and has been suggested to be an additional player in the interaction between the IGF-IGFBP-axis and metabolism., Study Design: We analyzed postnatal growth, metabolic parameters, and genotypes for the GHRd3-variant and IGFBP-1 -575G/A in 51 former extremely low birth weight preterm infants (mean age 5.9 years)., Results: GHRd3 but not IGFBP-1 -575G/A was significantly associated with postnatal growth velocity. Catch-up growth, GHRd3, and IFGBP-1 -575G/A did not influence fasting insulin or HOMA-IR. However, we found significantly higher HbA1c and lower IGFBP-1 concentrations in GHRd3-carriers, a finding not seen with respect to IGFBP-1 -575G/A. Interestingly, HbA1c and IGFBP-1 levels also did not differ between children either with or without catch-up growth., Conclusions: In addition to an association with catch-up growth, GHR exon 3 genotype significantly modulates HbA1c and IGFBP-1 concentrations in former ELBW infants. In order to confirm this observation and to clarify whether the GHRd3-variant might be considered as an independent modulator of the low birth weight infant's risk to develop insulin resistance later in life, larger studies extending to later ages are required., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Chemokines are known to regulate the steady-state and inflammatory migration of cutaneous dendritic cells (DCs). The beta-chemokine CCL17, a ligand of CCR4, is inducibly expressed in a subset of DCs and is strongly up-regulated in atopic diseases. Using an atopic dermatitis model, we show that CCL17-deficient mice develop acanthosis as WT mice, whereas dermal inflammation, T helper 2-type cytokine production, and the allergen-specific humoral immune response are significantly decreased. Notably, CCL17-deficient mice retained Langerhans cells (LCs) in the lesional skin after chronic allergen exposure, whereas most LCs emigrated from the epidermis of allergen-treated WT controls into draining lymph nodes (LNs). Moreover, CCL17-deficient LCs showed impaired emigration from the skin after exposure to a contact sensitizer. In contrast, the absence of CCR4 had no effect on cutaneous DC migration and development of atopic dermatitis symptoms. As an explanation for the major migratory defect of CCL17-deficient DCs in vivo, we demonstrate impaired mobility of CCL17-deficient DCs to CCL19/21 in 3D in vitro migration assays and a blockade of intracellular calcium release in response to CCR7 ligands. In addition, responsiveness of CCL17-deficient DCs to CXCL12 was impaired as well. We demonstrate that the inducible chemokine CCL17 sensitizes DCs for CCR7- and CXCR4-dependent migration to LN-associated homeostatic chemokines under inflammatory conditions and thus plays an important role in cutaneous DC migration.

Modern intensive care techniques have led to higher survival rates of extremely low birth weight infants (ELBW, birth weight <1,000 g). Previous studies have suggested a link between abnormal birth parameters and subsequent endocrine disturbances, but a possible impact on bone maturation during childhood has not been studied. ELBW children were studied (mean chronological age (CA), 6.01 years; range, 4.5-8.2). Skeletal maturation was assessed according to Greulich and Pyle (8). Bone age (BA) was defined as retarded when DeltaBA-CA was < -1 SD and accelerated when DeltaBA-CA was >+1 SD. BA was either retarded or accelerated in 15 patients (24.6%). Twenty-one of 61 radiograms (34.4%) showed a discordant BA with a marked gender difference (14/24 boys; 7/37 girls). DeltaBA-CA correlated significantly with BMI (r = 0.36; p = 0.005) and height SDS (r = 0.35; p = 0.006). We found significant correlations between BA and androgens. Insulin-like growth factor binding protein-1 (IGFBP-1), which decreases in insulin-resistant individuals, correlated negatively with BA. In conclusion, bone maturation in ELBW children is correlative with height and weight. It is modulated by a variety of metabolic factors, including IGFBP-1 and androgens. Bone age, together with height and weight catch-up, can thus possibly serve as early indicators of insulin resistance later in life.

Langerhans cells (LCs) and dermal dendritic cells (dDCs) are the professional antigen-presenting cells of the skin. Recently, their immunogenic versus tolerogenic role has come under re-investigation. LCs are distinguished from dDCs by Langerin (CD207) staining or by detection of Birbeck granules. However, for in vitro experiments it is desirable to have a simple and robust flow cytometric demarcation of both cell types. We show here that CD24a is expressed on LCs but not on dDCs isolated directly from the skin. Moreover, in combination with major histocompatibility complex class II (MHCII), CD24a expression levels distinguish LCs from dDCs in skin-draining lymph nodes after antigen activation and migration. High expression of CD24a correlated strictly with CD207 expression. MHCII(high) cells were unique for skin-draining lymph nodes and were shown to be the only cells carrying antigen after FITC painting of the skin. CD24a expression levels further differentiated LCs and dDCs in the MHCII(high) population. As staining for CD24a does not require fixation of cells, CD24a-stained cells can be used for in vitro experiments to analyze and compare the functional roles and properties of dDCs and LCs.

Background: Preterm infants with very low birth weight frequently exhibit impaired longitudinal growth during the first years of life. Recently, the d3-isoform (genomic deletion of exon 3) of the GH receptor (GHR) has been linked to an increased responsiveness to GH., Objective: Our objective was to test whether the GHRd3 isoform is associated with postnatal catch-up growth in very low birth weight preterm infants., Design and Patients: We compared the postnatal growth pattern of 77 otherwise healthy preterm infants (mean gestational age, 28.5 wk; range, 23-35 wk) with a birth weight below 1500 g (mean birth weight, 941 g) to their GHR exon 3 genotype, which was analyzed by multiplex PCR. On examination, mean age of the children was 6.0 yr (range, 4.2-8.0 yr)., Results: Children homozygous or heterozygous for the GHRd3 allele showed a significantly higher rate of postnatal catch-up, compared with those homozygous for the full-length allele., Conclusions: Our results define the GHR exon 3 genotype as a predictor for the postnatal growth pattern of very low birth weight preterm infants. Those who carry at least one GHRd3 allele are more likely to catch-up.

The ligand-activated aryl hydrocarbon receptor (AHR) is known to modulate many genes in a highly cell-specific manner, either directly or indirectly via secondary effects. In contrast, little is known about the effects of AHR deficiency on gene expression balance. We compared the transcriptome of CD4 T cells from AHR-/- mice and wild-type mice; 390 genes, many of them immunotypic, were deregulated in AHR-deficient CD4 cells. TCDD-induced transcriptome changes correlated with the AHR expression level in immune cells. However, there was little overlap in AHR-dependent transcripts found in T lineage cells or dendritic cells. Our results demonstrate flexible gene accessibility for the AHR in immune cells. The idea of a universal battery of AHR-responsive genes is not tenable.